In recent years, there have been advances in the technology of blood purification, particularly the technology of removing humoral factors from blood, for the purposes of treatment of inflammatory diseases or pretransplant immunosuppression.
In Patent Document 1, an approach is made in which a water-insoluble material is used as a material for removing or inactivating cytokines that are one kind of proteins, in which water-insoluble material, a urea bond and an amino group; or a urea bond, an amide group, and an amino group; or an amide group, an amino group, and a hydroxyl group are introduced on a substrate composed of a polymer material.
Patent Document 2 discloses a water-insoluble material in which an amide group and an amino group suitable for removing high-mobility group proteins are introduced. The Patent Document 2 reports that an amino group content which is too small does not afford desired adsorptive performance, and an amino group content which is too large deteriorates the physical strength of the water-insoluble carrier and also tends to reduce the adsorptive performance, and accordingly, the content is preferably 0.03 μmol to 1 mmol, more preferably 0.1 μmol to 0.1 mmol, per 1 g weight of the water-insoluble carrier.
Patent Document 3 discloses a material for blood purification, in which 50 μm or less fibers are used. The Patent Document 3 reports that an amino group content which is too small tends not to express the function of the group, and an amino group content which is too large tends to reduce the physical strength of the fabric structure, and accordingly, the content is preferably 0.01 to 2.0 mol, more preferably 0.1 to 1.0 mol, per a repeating unit of the polymer.
In Patent Document 4, as for a separation membrane for artificial kidneys, an attempt has been made to increase an adsorption amount of an oxidized LDL by grafting a hydrophilic polymer containing an amide group, and polyethyleneimine on the surface of a substrate.
Here, cytokines refer to a group of proteins which, through a stimulus such as infection or trauma, are produced from various cells such as immunocompetent cells, released extracellularly, and allowed to act. Many are known, including interferon-α, interferon-β, interferon-γ, interleukin-1β, interleukin-1 to interleukin-15, tumor necrosis factor-α, tumor necrosis factor-β, high-mobility group box-1, erythropoietin, monocyte chemotactic factors, and the like. Cytokines are considered to be originally substances that organisms produce for biophylaxis, but it has been made clear that a group of proteins such as tumor necrosis factor-β, interleukin-6, interleukin-8, and monocyte chemotactic and activating factors, when excessively produced, get involved with tissue damage and pathology in various inflammatory diseases. For example, there is a report that administering tumor necrosis factor-β to an animal induces septic shock, and accordingly it is useful for improvement of pathology to inhibit the action of the tumor necrosis factor.
In the case of hypercytokinemia (for example, human sepsis), in which a high concentration of free cytokines are present in blood, the concentrations of interleukin-6 and interleukin-8 in blood increase remarkably (Non Patent Document 1 and Non Patent Document 2), and it is recognized that the concentrations of these in blood correlate with pathology and prognosis. In addition, it is pointed out that, in autoimmune diseases such as rheumatoid arthritis, allergic diseases, and the like, excessive production of interleukin-6 and interleukin-8 is involved with pathology.
On the other hand, in order to treat the above-mentioned inflammatory diseases by inhibiting the action of cytokines, an attempt has been made to administer to a living body a protein, such as typified by an antibody or a soluble receptor, that specifically binds to a target cytokine to inhibit its action; or a protein, such as a receptor antagonist, that binds to the receptor of a cytokine competitively with the cytokine.
In Non Patent Document 3, an attempt is made to remove cytokines from blood with a blood purification therapy using an artificial kidney.
Furthermore, recent interest has focused on an activated leukocyte-activated platelet complex as a new causative substance of inflammatory diseases. It is reported that the activated leukocyte-activated platelet complexes have a higher chemotactic activity to tissues exhibiting an inflammatory reaction compared with an activated leukocytes alone, and release more histotoxic substances, and that the interaction between an activated platelet and an activated leukocyte increases the release of histotoxic substances by the activated leukocyte (Non Patent Document 4).